Insulin-like peptide 5 (INSL5) targets the G protein-coupled receptor, relaxin family peptide receptor 4 (RXFP4), predominantly coexpressed in the colorectum. While INSL5 also binds to the related receptor RXFP3, it does not activate it. The INSL5/RXFP4 axis is a promising target for treating gastrointestinal disorders such as constipation. Despite its therapeutic potential, the clinical application of INSL5 has been hindered by synthesis complexities, necessitating the need for more accessible yet potent mimetics. In this study, we engineered an INSL5 analogue A13:B7-24-GG, featuring a simplified two-chain, two-disulfide scaffold with 32 amino acids, as opposed to the 45 amino acids found in native INSL5 (two-chain, three-disulfide), improving the synthesis yield by 19.5-fold. Additionally, A13:B7-24-GG demonstrates ∼4-fold higher potency (EC = 1.17 nM vs 4.57 nM) and ∼11 times greater selectivity than native INSL5, with significantly reduced RXFP3 binding affinity, positioning it as a promising new therapeutic candidate for the treatment of constipation.
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